Di-methyl-butylsulfamylbenzoic acid



Patented Aug. 26, 1952 ol-murnrt-no'rig sgtrmrrnnuzolo Carl Ziegler,Clementon, N. J assignor to Sharp & Dohme, Incorporated, Philadelphia,Pa., a

corporation of Maryland No Drawing. Application June 28, 1950,

' Serial No. 170,943

2 Claims. (01. 167-55) This invention relates to a new compound which isellective as an adjuvant for use in conjunction with the administrationof penicillin to provide an increase in the blood plasma penicillinconcentration with a given dose of penicillin, thereby making possiblevery high penicillin blood levels, or permitting the use of smallerquantities of penicillin for providing a given blood level, orpermitting the less frequent administration of penicillin whilemaintaining a penicillin blood level adequate for bactericidal orbacteriostatic purposes. The invention also relates to the preparationof various dosage forms in which this new compound is incorporated foradministration by various routes.

Penicillin appears to be almost quantitatively excreted from the bloodby' the epithelial cells of the tubules, at least within plasmaconcentrations which have been explored, with the result that its rateof excretion from the blood stream is approximately five times that ofmaterials which are excreted by glomerular filtration, alone, thetubular excretion accounting for about 80 (81)% and the glomeruli about20 (19) Various proposals have been made to overcome the difficultiesdue to the rapid elimination of penicillin, such as the administrationof it in sus ension in an oleaginous material, the mixture beingadministered by intramuscular injection. A second proposal which, hasbeen made has been to use a material such as diodrast orparaaminohippuric acid which, like penicillin, is selectively excretedby the tubules. Neither of these proposals has afforded asatisfactorysolution to the problem, since the use of an oleasinous suspension ofpenicillin merely prolongs the time interval between injections and doesnot provide a high blood level of penicillin and, while the secondproposal provides ameans to inhibit the excretion of penicillin by thekidney tubules to a substantial extent, it does so at the expense ofoverloading the tubules with ma-- terials which they function to removefrom the blood.

The present invention is based upon the discovery that removal orpenicillin from the blood stream by the kidney tubules can beeffectively blocked by the new adjuvant 01 this invention,

4 2 para (1,3 dimethylbutylsulfamyl) beuzoic acid, having the generalformula P i one-on on on Ni.-sor -ooog and its salts.

The new suli famyl benzolc acid of the invention is generally made byfirst preparing a paracarboxybenzenesultonyl halide by oxidation of'para toluenesulfonyl halide, or bypreparing para-cyanobenzenesulionylhalide by treating para-sulfamyl benzoic acid with phosphoruspentachloride. The para carboxybenzenesulfonyl halide or paracyanobenzenesulfonyl halide thus formed is reacted with the1,3-dimethylbutylamine, advantageously using an excess, for example, twoto three equivalents, of the amine,

and when the cyanobenzenesulfonyl halide reactant is used, hydrolyzingthe product thus formed to the corresponding carboxyl derivative. Thereaction is preferably carriedout in the presence of a solvent, such asacetone or pyridine and the like, or in aqueous sodiumhydroxide, andpreferably with cooling, Any by-product formed during the reaction isremovedby treatme the reaction medium with a weak, alkaline substance,such as an aqueous sodium bicarbonate solution, filtering off theprecipitated byroduct, and then recovering thepara-(1,3-dimethylbutylsulfamyl) -benzoic acid Irom the illtrate byacidification.

The pr par tion of the new compound of the v invention is illustratedby, but notlrestricted to the following example:

Example Ir- PGTG r (1,3 dimethylbutylsub famyb bene oic acids 'ro 20.2grams (0.2 mol) or 1,3dimethyl-butylamine dissolved in 200 cc. ofacetone, contained in an open flask provided with a stirrer, 22.1 grams(0.1 mol) of paracar boxybenzenesulfonyl chloride was added in pertionswith cooling and stirring. The stirring was continued for an additionalone-half hour and the acetone then removed under vacuum. 300, cc, ofcold water was added to the residue and the solution made acid withhydrochloric acid. The precipitate was removed by filtration andredissolved in a sodium bicarbonate solution, Some insoluble materialwas removed by filtration and the filtrate treated with hydrochloricacid, precipitating grams of the crude product. After recrystallizationfrom dilute alcohol, 9 grams of the purified product, melting at 207-208C., was obtained.

An alternate method for preparing this compound is illustrated by thefollowing example:

Example II. Para- (1,3-dimethylbutylsulfamyl)-bensoic acid.-20.1 grams(0.1 mol) of paracyanobenzenesulfonyl chloride was added to 20.2 grams(0.2:mol) of 1,3-dimethyl-butylamine in 50 cc. of pyridine. The mixturewas allowed to stand overnight at room temperature after which it waspoured into 500 cc. of ice water containing 50 cc. hydrochloric acid.The yellow oil which separated later solidified yielding 24 grams ofcrude para- (1,3-dimethylsulfamyl) -benzonitrile composition comprisingboth penicillin and the adjuvant, a ratio of about 0.5 gram of adjuvantto from 25,000 to 200,000 units of penicillin is advantageous.

In general, oral administration of the adjuvant at the rate of 4 to 16grams per day is adequate to suppress the rate of penicillin excretionto an extent such that the blood level with a given dose of penicillinadministered orally or intramuscularly in aqueous solution .will beincreased to as much as four times the level obtained without the use ofthe adjuvant.

The adjuvant may be prepared in any con- "venient dosage form, eitheralone or admixed with penicillin, such as in a compressed tablet, a dryfilled capsule or a soft elastic capsule. It

7 is to be understood, of course, that other inwhich, after threerecrystallization's from isopropyl ether, melted at 79-80 C. The thusobtained benzonitrile was added to 150 cc. of a 10% sodium hydroxidesolution and refluxed for two hours. The mixture was then treated withdecolorizing charcoal, filtered and the filtrate treated withhydrochloric acid thereby producing a whiteprecipitate. Afterfiltration, the solid material was redissolved ina sodium bicarbonatesolution and reprecipitated by the adition of hydrochloric acid. Aftertwo recrystallizations .gredients','such as binders, diluents,excipients, I antacid'substances, or other inert or therapeuticallyactive compounds may be incorporated into any selected dosage form alongwith the ad- -juvant or adjuvant plus penicillin, provided the fromdilute alcohol the para-(1,3-dimethylbutylsulfamyl) benzoic acid meltedat 208209 0. Yield 13.5 grams.

The para- (1,3-dimethylbutylsulfamy1) benzoic acid of this invention isrelatively non-toxic, it is soluble in blood plasma and operates, whencarried-by the blood. stream into contact with the tubules, to preventtheir normal action in removingpenicil-lin fromlthe blood stream. Theadjuvant itself isanotiexcretedto any substantial extent bythe tubules,and the available evidence indicates that on coming into' contact 'withthe epithelial cells of the tubules, it operates to block their actionby, interference with the normal functioning of the epithelial cells anddoes not inhibit the excretion ofthe. penicillin by competing with itwithin the. tubular functional capacity. Thus, the adjuvant is efiectivein eliminating or. very radicallyireducing tubular excretion ofpenicillin in rplasma 1 concentrations around 10 mg. per 100' cc., whichisabout the threshold value for'agents such as p'-aminohip- .purie acidor diodrast. The highly effective adjuvant of this invention.will'reduce the excretion of' penicillin by the tubule's,at a bloodplasma concentration of about 10 mg. per 100 cc. to almost Zero, so"that the actual elimination of penicillin from the blood stream becomessubstantiallythat resulting from glomerular filtration, that is, aboutone-fifth the normal rate (ignoring plasma binding). The adjuvant itselfis eliminated by the glomeruli'.

The adjuvant can be administered orally or, when dissolved in an aqueoussolution, it can be administered intravenously or 'intramuscularly, andin either case, in admixture with penicillin or separately therefrom.

Whether the 'adjuvant is administered in admixture with or separatelyfrom the penicillin, the quantity used should be such as to provide aconcentration in the blood stream of adjuvant adequate to blocksubstantially the excretory mechanism of the tubules. Maximum efiectwill be obtained with blood plasma concentrations of about 5 to 15mg.per 100 cc., obt ainable at dosage levels of about 4 to 16 grams perday orally and somewhat less than this intravenously. In a addedingredient does not destroy the activity of either'the adiuvant orpenicillin. Similarly, the adjuvant and, if desired, the penicillin maybe dispersed in'an oleaginous base either alone or along with othersuitable substances and filled into soft elastic capsules or an aqueoussolution may be prepared and filled into ampuls. Other suitabledosage'forrns will be readily apparent to those skilled inthe art, andit is not, the purpose of this discussion to limit the mode of packagingor administration to the example specifically described below. 7

C'ompresscdtablets Part I.4,548' grams-of corn starch are hydrolyzedwith 40 liters of hot water. 50,000 grams of para (1,3dimethylbutylsulfamyl) benzoic acid are added tothe wet paste and theentire mass is then granulated. The wet granulated material is passedthrough a coarse screen, spread thinly'on-trays and dried in an oven atabout 60. C. for 24 hours and then passed through a No. 14 screen.

a low viscosity, e. g.,. 20 centipoise)- are dissolved in 3.5 liters ofanhydrous alcohol with the aid of gentle heating and in an atmospherecontrolled at 30% relative humidity at 25 C. In a separate container 6,666 grams of penicillin G sodium, 5,425 grams of powdered sodiumbicarbonate and 1,618 grams of dried corn starch are intimatelymixedtogetherand then passed through a fine screen. This mixed powder isgranulated with the Warm solution of ethyl cellulose, adding additionalanhydrous alcohol, if necessary, to form good granules. The granulatedmaterial is passed through a coarse-screen, spread on trays and dried inan oven at 55 C. for 14 hours and then passed through a Noj20's'cr'een;Y

The granules obtained in Part I and Part II are combined and mixed with4,927 grams of granular sodium bicarbonate and then 6,660 grams of driedcorn starch are intimately mixed therein. After thorough stirring,7',000 grams of dried talc and 525 grams-of magnesium stearate are addedand the mixture again thoroughly stirred. This final mixture --iscompressed into tablets using a onehalf inch die and flat face, doubleedge punches yielding 100,000 tablets each weighing 0.875 gram andcontaining 0.5 gram of para-(l.,3-dimethyl butylsulfamyl) eb'enzoi'cacid and 100,000 units (plus 10% excess) of penicillin G sodium.

In compositions containing penicillin, it is advisable, in accordancewith customary practice, to include an excess of the penicillin, forexample, a ten per cent excess over the label-claimed quantity inaccordance with present practice. An excess of penicillin introduces nodifficulty save its cost. The penicillin used may be any of the formsavailable for use, such as the calcium, sodium, potassium, procaine, andthe like salts of amorphous or crystalline penicillin.

Having now particularly described the invention, what is claimed is:

1. An adjuvant which is a member of the group consisting ofpara-(1,3-dimethylbutylsulfamyl) benzoic acid having the formula CH3 CH3l l CHa--CHCHz-CH and its non-toxic, water-soluble salts.

2. A composition suitable for therapeutic use, comprising penicillin andan adjuvant which is a member of the group consisting of para-(1,3-dimethylbutylsulfamyl) -benzoic acid having the formula CH3 CH3REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,162,211 Andersen June 13, 1939OTHER REFERENCES Reid: Prolongation of Penicillin Activity withPenicillir1ase-1nhibiting Compounds, Proc. Soc. Exptl. Biol. and Med,November 1946, pp. 438-443. 167/6'5 p.

So-Hoo: Activity of Penicillin Combined with Other Anti-StreptococcalAgents Archives Biochemistry. September 1944, pages 99-106. 167/65 p.

Meads: Caronamide and Penicillin, J. Am. Med. Assoc., November 20, 1948,pages 874-877.

Pratt et al.: Antibiotics, Lippincott Co., 1949, pages 112416. (Book inDivision 43.)

2. A COMPOSITION SUITABLE FOR THERAPEUTIC USE, COMPRISING PENICILLIN ANDAN ADJUVANT WHICH IS A MEMBER OF THE GROUP CONSISTING OFPARA-(1,3DIMETHYLBUTYLSULFAMYL)-BENZOIC ACID HAVING THE FORMULA